PepT1-/- microbiota therapy as a treatment for colitis

PepT1-/- 微生物群疗法作为结肠炎的治疗方法

• 批准号: 10655304
• 负责人: DIDIER MERLIN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655304
• 关键词: Adult; Affect; Alginates; Anti-Inflammatory Agents; Bacteria; Cell physiology; Cells; Colitis; Colon; Colorectal Cancer; Crohn' s disease; Data; Diagnosis; Down-Regulation; Drug Delivery Systems; Engraftment; Epithelial Cells; Etiology; Foundations; Funding; Future; General Population; Genetic; Goals; Healthcare; Hydrogels; Immune system; Inflammation; Inflammatory; Intestinal permeability; Intestines; Large Intestine; Mediating; Membrane Transport Proteins; Metabolic; MicroRNAs; Modification; Mucosal Immune Responses; Mucous body substance; Mus; Oligopeptides; Oral; Oral Administration; Oral Examination; Pathologic; Patients; Peptides; Phenotype; Population; Predisposition; Prevention; Proteomics; Protons; Research; Role; Severities; Small Intestines; Testing; United States National Center for Health Statistics; Up-Regulation; Variant; Veterans; Wild Type Mouse; cell type; cellular targeting; colitis associated cancer; dextran sulfate sodium induced colitis; experimental study; fecal transplantation; gain of function; genome-wide; gut inflammation; in vivo; intestinal epithelium; intestinal homeostasis; loss of function; member; metabolome; microbiota; microbiota transplantation; military veteran; mouse model; murine colitis; nanoparticle; novel; prevent; response; therapeutic development; tumorigenesis

PepT1, which is a member of the proton oligopeptide transporter (POT) superfamily, is well known to transport di/tripeptides. Our group and others have shown that PepT1 is highly expressed in epithelial cells of the small intestine, but present at low or undetectable levels in such cells of the normal large intestine. In addition, we have demonstrated that colonic PepT1 expression is up-regulated in colitis and colitis-associated cancer (CAC). By generating gain- and loss-of-function mouse models with PepT1 expression specifically in intestinal epithelial cells (IECs), we explored the role of PepT1 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. We also examined the expression and transport activities of PepT1, using mouse models of colitis and CAC, and further revealed that the function of this membrane transporter is not restricted to its classical function as a transporter of di-tripeptides. For example, we demonstrated that PepT1 expression helps maintain intestinal homeostasis by mediating intestinal miRNA expression/secretion. Importantly we demonstrated during the last funding cycle that the PepT1-/- microbiota/metabolome is sufficient to protect against colitis and CAC. The overall goal of the current proposal is to develop a drug delivery platform to treat colitis. The initial aim of this proposal will be to investigate whether oral delivery of alginate hydrogel-loaded PepT1-/- microbiota will enhance the engraftment dynamics/diversity of the donor microbiota and consequently enhance the prevention/treatment of colitis. In the second aim, we will explore the cellular targets of PepT1-/- microbiota and assess the subsequent intestinal cellular responses that decrease colitis. Finally, we will characterize and assess the in vivo colitis-preventing effects of oral administration of specific anti-inflammatory metabolites from PepT1-/- microbiota loaded into nanoparticles. The proposed research will facilitate the development of therapeutic solutions targeting intestinal inflammatory and colitis associated cancer conditions.

PepT1是质子寡肽转运蛋白（POT）超家族的一员

项目成果

Co-delivery of camptothecin and curcumin by cationic polymeric nanoparticles for synergistic colon cancer combination chemotherapy.

阳离子聚合物纳米颗粒共同递送喜树碱和姜黄素用于协同结肠癌联合化疗

• DOI: 10.1039/c5tb01245g
• 发表时间: 2015-10-21
• 期刊: Journal of materials chemistry. B
• 作者: Xiao B;Si X;Han MK;Viennois E;Zhang M;Merlin D
• 通讯作者: Merlin D

Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer.

• DOI: 10.1016/j.biomaterials.2016.06.018
• 发表时间: 2016-09
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Zhang M;Viennois E;Prasad M;Zhang Y;Wang L;Zhang Z;Han MK;Xiao B;Xu C;Srinivasan S;Merlin D
• 通讯作者: Merlin D

PepT1 Expression Helps Maintain Intestinal Homeostasis by Mediating the Differential Expression of miRNAs along the Crypt-Villus Axis.

• DOI: 10.1038/srep27119
• 发表时间: 2016-06-01
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Zhang Y;Viennois E;Zhang M;Xiao B;Han MK;Walter L;Garg P;Merlin D
• 通讯作者: Merlin D

Inhibition of MDR1 gene expression and enhancing cellular uptake for effective colon cancer treatment using dual-surface-functionalized nanoparticles.

• DOI: 10.1016/j.biomaterials.2015.01.014
• 发表时间: 2015-04
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Xiao, Bo;Zhang, Mingzhen;Viennois, Emilie;Zhang, Yuchen;Wei, Na;Baker, Mark T.;Jung, Yunjin;Merlin, Didier
• 通讯作者: Merlin, Didier

Oral administration of pH-sensitive curcumin-loaded microparticles for ulcerative colitis therapy.

• DOI: 10.1016/j.colsurfb.2015.07.081
• 发表时间: 2015-11-01
• 期刊: Colloids and surfaces. B, Biointerfaces
• 作者: Xiao B;Si X;Zhang M;Merlin D
• 通讯作者: Merlin D